SMC1A was first reported in relation to X-linked Cornelia de Lange syndrome in 2006 (Musio et al., PMD: 16604071). Variants in SMC1A have been reported in individuals with the following disease entities: Cornelia de Lange syndrome 2 (OMIM: 300590) and Developmental and epileptic encephalopathy 85, with or without midline brain defects (OMIM: 301044); both are associated with X-linked dominant inheritance. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no difference in inheritance pattern and overlapping phenotypes. Therefore, these two disease entities have been lumped into one disease entity, X-linked complex neurodevelopmental disorder.
At least 20 missense variants, 1 splicing, and 5 small deletions have been reported in humans. Variants have been found in at least 28 probands in 5 publications (PMIDs: 28166369, 26752331, 24124034, 1660407, 19701948). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is also supported by functional alteration in patient cells and protein interactions.
In summary, there is definitive evidence supporting the relationship between SMC1A and X-linked complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on June 19, 2019 (SOP Version 6).
The SMC1A gene has been associated with X-linked complex neurodevelopmental disorder. Variants in SMC1A have been reported in humans as early as 1995 (7757075, 7757074, 7757076). This disease association was made using case-level data and experimental data. At least 20 missense, 1 splicing, and 5 small deletions have been reported in humans. Variants have been found in at least 28 probands in 5 publications (28166369, 26752331, 24124034, 1660407, 19701948). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is supported by patient cells functional alteration and protein interactions. In summary, SMC1A is definitively associated with X-linked complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 6/19/19 (SOP Version 6).
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